Novel Immunoregulatory Drugs for Type 1 Diabetes BioTherapeutics, Inc (BTI) is an emerging biotech company that synergistically combines the power of advanced computational modeling with translational experimentation to accelerate the development of novel products for precision medicine and health. Lead molecule, BT-11, is a novel small molecule targeting the LANCL2 pathway in IBD with two open INDs, completed Phase I and initiated Phase II clinical testing in 2019. Type 1 Diabetes (T1D) is an immune-mediated disease that afflicts three million Americans. Each year, more than 40,000 individuals are diagnosed with T1D in the U.S. with 90% of these diagnoses occurring in youths who will be at risk for many co-morbidities throughout life even with well-regulated insulin therapy. Over the last 10 years, there has been a 3-5 percent annual increase in the prevalence of T1D under the age of 20. We have discovered a naturally occurring isoprenoid, abscisic acid (ABA) that modulates immune responses and increases insulin sensitivity. LANCL2 is the molecular target of ABA. We have developed novel LANCL2 ligands such as BT-11 and BT-63 that exert potent immunoregulatory and anti-diabetic activity in mouse models of IBD and T1D. This project will evaluate the efficacy and safety of novel LANCL2 ligands for treating T1D. The Specific Aims for the proposed SBIR Phase I application are to: (1) Identify the safety profile of BT-63. We have identified immunologically active, LANCL2-specific systemically distributed ligands. We will conduct safety analysis in a 21-d repeat dose study in rats on BT-63. (2) Evaluate the in vivo therapeutic efficacy of novel LANCL2 ligands in the NOD mouse model of T1D. NOD mice will be dosed with LANCL2-activating BT-63 at three dose levels to identify its ability to regulate glucose and insulin levels, provide pancreatic islet protection and improve survival. Ligands will be dosed in prophylactic and therapeutic (post-hyperglycemia development) capacities to assess therapeutic efficacies. (3) Determine the immunomodulatory and protective effects of LANCL2 ligands on human samples. We will test the efficacy of BT-63 in vitro on the prevention of damage to human islets and the generation of anti- inflammatory/regulatory responses in human PBMCs from T1D donors. Expected successful outcomes will include: i) a NOAEL ? 500 mg/kg oral dosing in rats, ii) ?20% increase in ? cell mass in vivo after BT-63 dosing, and iii) ? 50% reduction in IFN? at ? 100 nM in human primary cells. The SBIR Phase II will perform mechanistic and translational studies pertaining to T1D pathogenesis including auto-antigen recognition and antioxidant enzyme activity, further investigate the role of LANCL2 in T1D plus progress lead molecules through IND-enabling safety and toxicology studies. Long Term Goal: The technology will address the overlying health problem with patients suffering from T1D and provide a significant commercialization potential to a market of 3 million estimated to be over $14.9 billion for T1D-associated healthcare costs in the U.S. each year.